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Nat Commun. 2017 Jun 28;8(1):39. doi: 10.1038/s41467-017-00049-x.

A novel humanized mouse lacking murine P450 oxidoreductase for studying human drug metabolism.

Barzi M1, Pankowicz FP1,2, Zorman B3, Liu X4, Legras X1, Yang D1,2, Borowiak M1,2,5,6,7,8, Bissig-Choisat B1,5, Sumazin P3,7, Li F4,5, Bissig KD9,10,11,12,13.

Author information

1
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX-77030, USA.
2
Graduate Program, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX-77030, USA.
3
Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX-77030, USA.
4
Alkek Center for Molecular Discovery, Advanced Technology Core, Baylor College of Medicine, Houston, TX-77030, USA.
5
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX-77030, USA.
6
Program in Developmental Biology, Baylor College of Medicine, Houston, TX-77030, USA.
7
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX-77030, USA.
8
McNair Medical Institute, Houston, TX-77030, USA.
9
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX-77030, USA. bissig@bcm.edu.
10
Graduate Program, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX-77030, USA. bissig@bcm.edu.
11
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX-77030, USA. bissig@bcm.edu.
12
Program in Developmental Biology, Baylor College of Medicine, Houston, TX-77030, USA. bissig@bcm.edu.
13
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX-77030, USA. bissig@bcm.edu.

Abstract

Only one out of 10 drugs in development passes clinical trials. Many fail because experimental animal models poorly predict human xenobiotic metabolism. Human liver chimeric mice are a step forward in this regard, as the human hepatocytes in chimeric livers generate human metabolites, but the remaining murine hepatocytes contain an expanded set of P450 cytochromes that form the major class of drug-metabolizing enzymes. We therefore generated a conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene combined with Il2rg - /- /Rag2 - /- /Fah - /- (PIRF) mice. Here we show that homozygous PIRF mouse livers are readily repopulated with human hepatocytes, and when the murine Por gene is deleted (<5%), they predominantly use human cytochrome metabolism. When given the anticancer drug gefitinib or the retroviral drug atazanavir, the Por-deleted humanized PIRF mice develop higher levels of the major human metabolites than current models. Humanized, murine Por-deficient PIRF mice can thus predict human drug metabolism and should be useful for preclinical drug development.Human liver chimeric mice are increasingly used for drug testing in preclinical development, but express residual murine p450 cytochromes. Here the authors generate mice lacking the Por gene in the liver, and show that human cytochrome metabolism is used following repopulation with human hepatocytes.

PMID:
28659616
PMCID:
PMC5489481
DOI:
10.1038/s41467-017-00049-x
[Indexed for MEDLINE]
Free PMC Article

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